Grant: CIHR - ICR / Cancer Research Society Partnership - Res. Grants - Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, associated with poor prognosis, high invasiveness, early relapse, and distant metastasis. This subtype, accounting for nearly 15% of breast cancers, is characterized by the absence of estrogen receptor alpha (ERa), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). As a result, effective therapies for TNBC are very limited, primarily relying on conventional chemotherapy. Although patients initially respond positively to chemotherapy, the lack of specific targets, poor cell differentiation, high molecular heterogeneity, and the tumor’s metastatic potential contribute to a five-year survival rate of only 30%. The aggressive nature of TNBC is largely driven by its abundant population of cancer stem or tumor-initiating cells, which enable metabolic adaptations that fuel tumor growth and metastasis. This proposal is inspired by our recent discovery that targeting the nuclear receptor liver receptor homolog-1 (LRH-1) through knockdown or small-molecule modulators significantly reduces TNBC aggressiveness. Our study shows that LRH-1 is associated with a TNBC-specific gene expression program linked to cancer progression, metastasis, and drug resistance. Although LRH-1 was initially thought to be constitutively active and not ligand-regulated, recent breakthroughs have led to the development of highly potent synthetic LRH-1 modulators with in vivo activity. Our preliminary data with this new lead LRH-1 modulator demonstrate a dramatic reduction in tumor-initiating cells, along with strong suppression of lipid and cholesterol metabolism and a marked decrease in cancer cell invasion capacity. Overall, our findings suggest exciting therapeutic potential for LRH-1 modulators in TNBC by targeting mitochondrial lipid and cholesterol metabolic programs essential for tumor-initiating cell survival and maintenance. Consequently, this modulator provides a unique opportunity to investigate the mechanisms and feasibility of targeting LRH-1 in TNBC. This proposal is structured around two specific aims: 1. To determine the role of LRH-1 in establishing the transcriptional program that regulates mitochondrial lipid and cholesterol metabolism in TNBC tumor-initiating cells. 2. To evaluate the therapeutic potential of LRH-1-targeting compounds in reducing TNBC recurrence and metastasis. To accomplish this, we will use LRH-1 modulators and genetic approaches to investigate LRH-1 function in TNBC and assess its potential as a therapeutic target. Our strategy integrates genomics, lipidomics, cellular biology, and detailed mechanistic studies in both spheroids (patient-derived xenograft organoids) and in vivo TNBC models. This proposal is both conceptually and technically innovative. We propose a novel function for LRH-1 in promoting TNBC aggressiveness by regulating metabolic pathways essential for tumor-initiating cells survival. Furthermore, the discovery of LRH-1- specific transcriptional plasticity in breast cancer suggests an additional layer of regulatory control, whereby this transcription factor establishes specific core regulatory networks driving oncogenesis. By combining genomic and metabolic analyses in TNBC spheroids (Aim 1) with the evaluation of in vivo efficacy (Aim 2), we aim to gain insights that could inspire new treatment approaches for TNBC.